N-alkylation of indole derivatives

ABSTRACT

The present invention provides methods for the efficient preparation of indole derivatives of the formula 
                 
 
wherein X is methyl or benzyl; and R 1 , R 2 , R 3  and R 4  are independently hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted alkyl, alkoxy, aralkoxy, carboxy, alkoxycarbonyl, aryl or heteroaryl; or R 1  and R 2  combined together with the carbon atoms to which they are attached form a fused 6-membered aromatic ring; by reacting indoles of the formula 
                 
 
wherein R 1 , R 2 , R 3  and R 4  have meanings as defined for formula I, with dimethyl carbonate when X is methyl, or with dibenzyl carbonate when X is benzyl, in the presence of a catalytic amount of a base at an ambient temperature to afford compounds of formula I wherein X, R 1 , R 2 , R 3  and R 4  have meanings as defined herein above. In particular, the present invention provides methylation and benzylation of the indole nitrogen in nearly quantitative yields using 1,4-diazabicyclo[2.2.2]octane as the base in a catalytic amount under mild conditions, wherein the alkylations may be conducted in the absence or the presence of an ionic liquid, under microwave irradiation or utilizing conventional heat, or combinations thereof.

This application claims the benefit of U.S. Provisional Application No.60/396,827, filed Jul. 18, 2002.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention provides highly efficient, catalytic methods forN-alkylation of indole derivatives, more specifically the methodprovides N-methylindole and N-benzyl-indole derivatives.

2. Description of Related Art

N-Methylindole derivatives, such as indole alkaloids, are importantnatural products that exhibit a wide array of biological activities. Forexample, affinisine has been shown to produce delayed intention tremors,marked central nervous system (CNS) depressant activity, ataxia,hypothermia and bradypnea (Liu et al., Tetrahedron Lett., 2000, 41,6299), and a synthetic pentacyclic indole analog has revealedantitumoral properties (Christophe et al., Tetrahedron Lett. 1998, 39,9431).

Common approaches to the synthesis of N-alkylindole derivativestypically require a two-step protocol: (1) formation of an active indoleanion by stoichiometric amount of a strong base; and (2) reaction of theresulting anion with a toxic and hazardous alkylating agent such asmethyl iodide, dimethyl sulfate, benzyl chloride or benzyl bromide (e.g.Hilton et al., J. Chem. Soc., Chem. Commun. 2001, 209; Tratrat et al.,J. Org. Chem. 2000, 65, 6773; and Ottoni et al., Tetrahedron 1998, 54,13915). Improved processes have been recently published utilizingnon-toxic reagents, however, under harsh and stoichiometric conditions(Bergman et al., Tetrahedron 1990, 46, 6113). It has been reported thatdimethyl carbonate may be employed effectively under milder conditionsto N-methylate indole derivatives, however, these methods still demandthe use of a stoichiometric amount of a base to achieve reasonableprocess efficiency (Shieh et al., Organic Lett. 2001, 3, 4279; and PCTApplication No. WO 01/81305). Thus, development of an efficient, safe,and ecologically friendly methods for alkylation of indoles stillconstitutes an important challenge.

SUMMARY OF THE INVENTION

The present invention provides methods for the efficient preparation ofindole derivatives of the formula

wherein X is methyl (Me) or benzyl (Bn), and R₁, R₂, R₃ and R₄ areindependently hydrogen, halogen, cyano, nitro, hydroxy, optionallysubstituted alkyl, alkoxy, aralkoxy, carboxy, alkoxycarbonyl, aryl orheteroaryl; or R₁ and R₂ combined together with the carbon atoms towhich they are attached form a fused 6-membered aromatic ring; byreacting indoles of the formula

wherein R₁, R₂, R₃ and R₄ have meanings as defined for formula I, withdimethyl carbonate (DMC) when X is methyl, or with dibenzyl carbonate(DBC) when X is benzyl, in the presence of a catalytic amount of a baseat an ambient temperature to afford compounds of formula I wherein X,R₁, R₂, R₃ and R₄ have meanings as defined herein above.

In particular, the present invention provides methylation andbenzylation of the indole nitrogen in nearly quantitative yields using1,4-diazabicyclo[2.2.2]octane (DABCO) as the base in a catalytic amountunder mild conditions, wherein the alkylations may be conducted in theabsence or the presence of an ionic liquid, under microwave irradiationor utilizing conventional heat, or combinations thereof.

Other objects, features, advantages and aspects of the present inventionwill become apparent to those skilled in the art from the followingdescription and appended claims. It should be understood, however, thatthe following description, appended claims, and specific examples, whileindicating preferred embodiments of the invention, are given by way ofillustration only. Various changes and modifications within the spiritand scope of the disclosed invention will become readily apparent tothose skilled in the art from reading the following.

DETAILED DESCRIPTION OF THE INVENTION

As described above, the present invention provides highly efficient,catalytic processes for the manufacture of N-methylindole andN-benzylindole derivatives.

Listed below are definitions of various terms used to describe thecompounds of the instant invention. These definitions apply to the termsas they are used throughout the specification unless they are otherwiselimited in specific instances either individually or as part of a largergroup.

The term “optionally substituted alkyl” refers to unsubstituted orsubstituted straight or branched chain hydrocarbon groups having 1 to 20carbon atoms, preferably 1 to 7 carbon atoms. Exemplary unsubstitutedalkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl andthe like. Substituted alkyl groups include, but are not limited to,alkyl groups substituted by one or more of the following groups: halo,hydroxy, cycloalkyl, alkanoyl, alkoxy, alkanoyloxy, amino, alkylamino,dialkylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, nitro,cyano, carboxy, alkoxycarbonyl, aryl, alkenyl, alkynyl, aralkoxy and thelike.

The term “alkenyl” refers to any of the above alkyl groups having atleast two carbon atoms and further containing a carbon to carbon doublebond at the point of attachment. Groups having two to four carbon atomsare preferred.

The term “alkynyl” refers to any of the above alkyl groups having atleast two carbon atoms and further containing a carbon to carbon triplebond double bond at the point of attachment. Groups having two to fourcarbon atoms are preferred.

The term “cycloalkyl” refers to optionally substituted monocyclichydrocarbon groups of 3 to 7 carbon atoms, each of which may besubstituted by one or more substituents such as alkyl, halo, oxo,hydroxy, alkoxy, alkylthio, nitro, cyano and the like.

Exemplary monocyclic hydrocarbon groups include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

The term “alkoxy” refers to alkyl-O—.

The term “alkanoyl” refers to alkyl-C(O)—.

The term “alkanoyloxy” refers to alkyl-C(O)—O—.

The terms “alkylamino” and “dialkylamino” refer to alkyl-NH— and(alkyl)₂N—, respectively.

The term “alkylthio” refers to alkyl-S—.

The term “alkylthiono” refers to alkyl-S(O)—.

The term “alkylsulfonyl” refers to alkyl-S(O)₂—.

The term “alkoxycarbonyl” refers to alkyl-O—C(O)—.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6 to 12 carbon atoms in the ring portion, such as phenyl,naphthyl, tetrahydronaphthyl, biphenyl and diphenyl groups, each ofwhich may optionally be substituted by one to four substituents such asalkyl, halo, hydroxy, alkoxy, alkylthio, nitro, cyano and the like.

The term “monocyclic aryl” refers to optionally substituted phenyl asdescribed under aryl.

The term “aralkyl” refers to an aryl group bonded directly through analkyl group, such as benzyl and phenethyl.

The term “aralkoxy” refers to an aryl group bonded directly through analkoxy group.

The term “heteroaryl” refers to an aromatic heterocycle, for examplemonocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl,benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzofuryl, and the like, optionally substituted by e.g. lower alkyl,lower alkoxy or halo.

The term “ionic liquid” refers to organic salts that are liquid at orclose to room temperature. They differ from common salts by havingunusually low melting points. Ionic liquids tend to be liquid over awide temperature range, they may be immiscible with a number of organicsolvents as well as water, depending on the anion, and they may beemployed as highly polar yet noncoordinating solvents. Furthermore,ionic liquids are nonvolatile and have essentially no vapor pressure.Most are air and water stable. The properties of the ionic liquids canbe tailored by varying the cation and anion, the most common are thosewith alkylammonium, alkylphosphonium, N-alkylpyridinium andN,N-dialkylimidazolium cations.

Many ionic liquids are formed by reacting a tertiary amine or anitrogen-containing heterocyclic ring, preferably a heteroaromatic ring,with an alkylating agent (e.g. an alkyl halide) to form a quaternaryammonium salt, and performing ion exchange or other suitable reactionswith various Lewis acids or their conjugate bases to form ionic liquids.Examples of suitable tertiary amines and heteroaromatic rings includetri-n-butylamine, trioctylamine, trioctadecylamine, substitutedpyridines, optionally substituted imidazoles and pyrroles. Thesecompounds may be alkylated with virtually any straight, branched orcyclic C₁₋₂₀ alkyl group, but preferably, the alkyl groups are C₁₋₁₆groups, since groups larger than this tend to produce low melting solidsrather than ionic liquids.

Counterions which have been used include chloride, bromide, iodide,chloroaluminate, bromoaluminate, tetrafluoroborate, tetrachloroborate,hexafluoro-phosphate, nitrate, trifluoromethanesulfonate,methylsulfonate, p-toluenesulfonate, hexafluoroantimonate,hexafluoroarsenate, tetrachloroaluminate, tetrabromoaluminate,perchlorate, hydroxide anion, copper dichloride anion, iron trichlorideanion, zinc trichloride anion, as well as various lanthanum, potassium,lithium, nickel, cobalt, manganese, and other metal containing anions.

Certain low melting solids may also be used in place of ionic liquids.Low melting solids are generally similar to ionic liquids but havemelting points between room temperature and about 80° C., or they areliquids under the reaction conditions.

Examples of ionic liquids as defined herein above aretetra-n-butylammonium chloride (TBAC), tetra-n-butylammonium triflate(n-Bu₄N⁺OTf⁻), tetra-n-butylammonium tetrafluoroborate (n-Bu₄N⁺BF₄ ⁻),tetra-n-butylammonium hexafluorophosphate (n-Bu₄N⁺PF₆ ⁻),1-n-butyl-3-methyl-imidazolium chloride (bmim⁺Cl⁻),1-ethyl-3-methylimidazolium chloride (emim⁺Cl⁻) and1-n-hexyl-3-methyl-imidazolium chloride (hmim⁺Cl⁻). Further examples ofionic liquids are described, e.g., in J. Chem. Tech. Biotechnol, 1997,68, 351; Chem. Ind., 1996, 68, 249; J. Phys. Condensed Matter, 1993, 5(supp 34B), B99; J. Mater. Chem., 1998, 8, 2627; and Chem. Rev., 1999,99, 2071.

The term “microwave irradiation” as used herein refers to microwaveregion of the electromagnetic spectrum corresponding to wavelengths from1 cm to 1 m and to frequencies from 300 MHz to 30 GHz. By InternationalConvention, however, domestic and industrial microwave ovens generallyoperate at greater than 900 MHz, preferably from about 2450 MHz to about2455 MHz, in order to prevent interference with RADAR transmissions andtelecommunications. Thus, the entire microwave region is not readilyavailable for heating applications. Sources of microwave irradiationinclude multimode ovens and monomode ovens which may be batch orcontinuous devices. A preferred monomode oven is a continuous-flowreactor, such as a Milestone ETHOS-CFR continuous-flow reactor.

The methods of the present invention provides efficient catalyticprocesses for the preparation indole derivatives of the formula

wherein X is methyl or benzyl, and R₁, R₂, R₃ and R₄ are independentlyhydrogen, halogen, cyano, nitro, hydroxy, optionally substituted alkyl,alkoxy, aralkoxy, carboxy, alkoxycarbonyl, aryl or heteroaryl; or R₁ andR₂ combined together with the carbon atoms to which they are attachedform a fused 6-membered aromatic ring; by reacting indoles of theformula

wherein R₁, R₂, R₃ and R₄ have meanings as defined for formula I, withDMC when X is methyl, or with DBC when X is benzyl, in the presence of acatalytic amount of a base, preferably DABCO, at an ambient temperature,preferably at a temperature ranging from about 80° C. to about 100° C.for N-methylation reactions, and from about 90° C. to about 150° C. forN-benzylation reactions, to afford compounds of formula I wherein X, R₁,R₂, R₃ and R₄ have meanings as defined herein above. More preferably,N-methylation reactions are carried out at a temperature ranging fromabout 90° C. to about 95° C., and N-benzylation reactions at atemperature of about 135° C. The reaction time may range from about 1 hto about 36 h for N-methylation, and from about 1 h to about 100 h forN-benzylation.

According to the methods of the present invention, alkylation of theindole nitrogen of compounds of formula II, wherein R₁, R₂, R₃ and R₄have meanings as defined herein above, may be conducted in the presenceor the absence of an organic solvent such as toluene, acetonitrile,N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) orN-methylpyrrolidinone (NMP), preferably DMF or DMA.

Alternatively, the alkylation reactions of the present invention may becarried out in the presence of an ionic liquid, preferably, TBAC. Theionic liquid may be employed as the reaction solvent, or it may be usedas an additive when the alkylations are conducted in an organic solvent,such as those described herein above, to enhance the reaction rates.Preferably, the alkylations, in particular, the N-benzylation reactionsare carried out in DMA in the presence of about one molar equivalent(equiv) of an ionic liquid.

In addition, microwave irradiation may be employed to enhance the ratesof the alkylation reactions of the present invention. The alkylationreactions may be conducted under microwave irradiation at a frequencyranging from 300 MHz to 30 GHz generating a reaction temperature whichranges from about 120° C. to about 300° C., preferably, from about 140°C. to about 250° C. Most preferably, the alkylations are conducted at atemperature of about 160° C. Preferably, the alkylations are carried outfor a period of microwave irradiation time ranging from about 1 secondto about 300 min, more preferably from about 5 min to about 30 min. Whenthe alkylations are carried out at a temperature greater than theboiling point of any of the components of the reaction mixture it may beadvantageous to apply higher pressure in order to prevent boiling ofeither the reactants or the solvent. Generally, the microwavealkylations are conducted under a pressure ranging from about 1 bar toabout 60 bar, preferably, from about 10 bar to about 35 bar, mostpreferably about 20 bar.

Preferably, the N-alkylation of indoles of formula II, wherein R₁, R₂,R₃ and R₄ have meanings as defined herein above, is carried out in amolar concentration (M) of the substrate ranging from 0.1 M to 1.0 M.

The molar ratio of the base to the, substrate of formula II initiallypresent in the reaction mixture ranges preferably from 0.01:1 to 0.5:1.More preferably, the molar ratio ranges from 0.05:1 to 0.15:1 forN-methylation reactions, and from 0.05:1 to 0.35:1 for N-benzylationreactions.

The effectiveness of DABCO as the base in the catalytic alkylation ofthe indole nitrogen of compounds of formula II, wherein R₁, R₂, R₃ andR₄ have meanings as defined herein above, using DMC or DBC as thealkylating agent under mild reaction conditions may be demonstrated with5-bromoindole of formula IIa. As illustrated in the Table 1 below, inthe presence of 0.1 equiv (10 mol %) of DABCO, the catalytic processdescribed herein above affords N-methylindole of formula Ia (X ismethyl, entry 5) quantitatively within 5 h when heated at 90° C.

TABLE 1 N-Alkylation of 5-bromoindole.^(a)

Entry X Time (h) Base % of IIa % of Ia % of III 1^(b) Me 5 None 100 0 02^(b) Me 5 n-Bu₃N 100 0 0 3^(b) Me 5 DMAP 14 12 73 4^(b) Me 5 DBU 9 6 845^(b) Me 5 DABCO 0 >99 0 6^(c) Bn 96 None 84 5 11 7^(c) Bn 96 DABCO 2080 0 8^(d) Bn 24 None 53 43 4 9^(d) Rn 24 DABCO 12 82 6 ^(a)Allreactions are conducted using 0.1 equiv of the base if not otherwiseindicated. The compound distributions are determined by HPLC analysis ofthe reaction mixture. The identity of the components is confirmed by ¹HNMR, ¹³C NMR and MS. ^(b)The reaction is conducted on 5 mmol scale in 1mL of DMF and 10 mL of DMC at 90° C. ^(c)The reaction is conducted on 2mmol scale in 4 mL of DMA and 3 mmol of DBC at 95° C. ^(d)The reactionis conducted on 2 mmol scale in 4 mL of DMA and 3 mmol of DBC at 135° C.

In contrast thereto, the N-methylation using 0.1 equiv ofN,N-dimethylamino-pyridine (DMAP) or 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) affords the methylcarbamate of formula III (X is methyl, entries 3and 4) as the major component of the reaction mixture. It should benoted that without any base catalyst or in the presence oftri-n-butylamine (n-BU₃N), the N-methylation generates no product at all(entries 1 and 2). Similarly, the catalytic process of the presentinvention provides N-benzylindole of formula Ia (X is benzyl, entries 7and 9) in good yield in the presence of only 0.1 equiv of DABCO. As thedata in Table 1 illustrate, the N-benzylation reactions are generallyslower than the corresponding N-methylations and require higher reactiontemperatures and longer reaction times under the reaction conditionsemployed herein.

The effect of a variety of ionic liquids on the reaction rates ofN-alkylation reactions of the present invention may be demonstrated withN-benzylation of indole derivative of formula IIb. As shown in Table 2,indole of formula IIb, i.e., carbazole, may be converted toN-benzylindole of formula Ib within 3 h in excellent yield in thepresence of one equiv of TBAC (entry 9). In comparison, theimidazolium-series of ionic liquids are less effective, and ionicliquids that contain a chloride anion consistently perform better thanthe ones containing a different counterion (entries 5 and 7 to 9).

TABLE 2 The effect of ionic liquids on the benzylation rate ofcarbazole.^(a)

Entry Ionic Liquid % of Ib^(b) 1 None^(c) 59 2 bmim⁺ OTf 28 3 bmim⁺ BF₄⁻ 34 4 bmim⁺ PF₆ ⁻ 28 5 bmim⁺ Cl⁻ 65 6 emim⁺ BF₄ ⁻ 28 7 emim⁺ Cl⁻ 66 8hmim⁺ Cl⁻ 79 9 TBAC 93 ^(a)All reactions, except entry 1, are conductedwith 2 mmol of IIb, 3 mmol of DBC, 0.6 mmol of DABCO, and 2 mmol of anionic liquid in 4 mL of DMA at 135° C. for 3 h. ^(b)The yields aredetermined by HPLC analysis of the reaction mixture at the end of thereaction time indicated. ^(c)Same as procedure a, except no ionic liquidis present.

The effect of an ionic liquid on the reaction rates of N-benzylationreactions according to the present invention is further illustrated inTable 3. In a typical experiment, a substrate (2 mmol), i.e., an indoleof formula II, DABCO (10-30 mol %), DBC (3 mmol), TBAC (2 mmol) in DMA(4 mL) are heated at 135° C. and the reaction is monitored by HPLC untila trace or no starting material is detected. As promoted by TBAC, thebenzylation rates for 5-bromoindole (IIa), carbazole (IIb) and theunsubstituted indole (IIc) are significantly improved as shown byimpressive reductions in reaction times to 0.5 h (entry 1), 3 h (entry2) and 2 h (entry 3), respectively. In the absence of TBAC, the samereactions take 24 h, 72 h and 45 h under otherwise identical reactionconditions.

TABLE 3 Reduction of reaction times of N-benzylation in the presence ofn-Bu₄N⁺Cl⁻.^(a) Thermal^(b) Ionic Liquid^(d) Microwave^(g) EntrySubstrate Product^(a) (time, yield)^(c) (time, yield)^(c) (time,yield)^(c) 1^(e) IIa

24 h, 79% 0.5 h, 83%  6 min, 76% 2^(f) IIb

72 h, 80%   3 h, 89% 18 min, 82% 3^(f) IIc

45 h, 82%   2 h, 80% 12 min, 70% ^(a)The identity of the benzylatedproducts is confirmed by ¹H and ¹³C NMR and MS. ^(b)General procedureusing conventional thermal heating: a reaction flask is charged with thesubstrate (2 mmol), DARCO (10-30 mol %), DMA (4 mL), and DBC (3 mmol).The mixture is heated at 135° C., and the reaction is monitored by HPLCuntil trace or no starting substrate is detected (reaction time).^(c)Isolated yield based on starting substrate. ^(d)Same as procedure b,except 1 equiv of TBAC is added to the reaction mixture. ^(e)10 mol % ofDABCO. ^(f)30 mol % of DABCO. ^(g)Gereal procedure using microwaveheating: A solution of the substrate (20 mmol), DBC (60 mmol), DABCO(10-30 mol %), TBAC (20 mmol) in CH₃CN (80 mL) is passed through aMilestone ETHOS-CFR continuous-flow reactor preheated to 160° C. at 20bar. The reaction products are analyzed by HPLC after each pass (6 min).

It may be required to introduce protecting groups to protect otherfunctional groups from undesired reactions with the reaction componentsunder the conditions used for carrying out the N-alkylation of theindole nitrogen of compounds of formula II. The need and choice ofprotecting groups for a particular reaction is known to those skilled inthe art and depends on the nature of the functional group to beprotected, the structure and stability of the molecule of which thesubstituent is a part and the reaction conditions.

Well known protecting groups that meet these conditions and theirintroduction and removal are described, for example, in McOmie,“Protective Groups in Organic Chemistry”, Plenum Press, London, N.Y.,1973; and Greene and Wuts, “Protective Groups in Organic Synthesis”,John Wiley and Sons, Inc., NY, 1999.

The following Examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. If not mentionedotherwise, the processes described herein above are conducted underinert atmosphere, preferably under nitrogen atmosphere. All evaporationsare performed under reduced pressure, preferably between about 5 and 100mmHg. The structure of products and starting materials is confirmed bystandard analytical methods, e.g. melting points (mp) and spectroscopiccharacteristics (e.g. MS, NMR). Abbreviations used are thoseconventional in the art.

EXAMPLE 1

To a solution of 5-bromoindole (1.0 g, 5.10 mmol) in DMC (10 mL), DABCO(0.057 g, 0.51 mmol) is added followed by DMF (1 mL). The resultingsolution is heated to 90-95° C. for 5 h. The reaction is cooled to RT,and diluted with ethyl acetate (EtOAc, 50 mL) and H₂O (50 mL). Theorganic layer is separated and washed in sequence with H₂O (50 mL), 10%aqueous citric acid (2×50 mL) and H₂O (4×50 mL). The organic layer isdried over anhydrous sodium sulfate (Na₂SO₄), filtered and concentratedunder vacuum to give 5-bromo-1-methylindole (about 1.06 g, 99%) as agolden colored solid: ¹H NMR (CDCl₃) δ7.72 (d, 1H), 7.26 (dd, 1H), 7.13(d, 1H), 7.00 (d, 1H), 6.39 (d, 1H), 3.71 (s, 3H); ¹³C NMR (CDCl₃)δ135.3, 130.1, 129.9, 124.2, 123.2, 112.6, 110.6, 100.5, 32.9; MS m/z209 [M+1]⁺.

EXAMPLE 2

To a solution of 5-methoxyindole (1.0 g, 6.79 mmol) in DMC (10 mL),DABCO (0.076 g, 0.68 mmol) is added followed by DMF (2 mL). Theresulting solution is heated to 90-95° C. for 7 h. The reaction iscooled to RT, and diluted with EtOAc (40 mL) and H₂O (40 mL). Theorganic layer is separated and washed in sequence with H₂O (50 mL), 10%aqueous citric acid (2×40 mL) and H₂O (4×40 mL). The organic layer isdried over anhydrous Na₂SO₄, filtered and concentrated under vacuum togive 5-methoxy-1-methylindole (about 1.06 g, 97%) as a solid: ¹H NMR(CDCl₃) δ7.21 (d, 1H), 7.09 (d, 1H), 7.00 (d, 1H), 6.87 (dd, 1H) 6.39(d, 1H), 3.84 (s, 3H), 3.73 (s, 3H); ¹³C NMR (CDCl₃) δ153.9, 132.1,129.3, 128.7, 111.8, 109.9, 102.4, 100.3, 55.9, 32.9; MS m/z 161 [M+1]⁺.

EXAMPLE 3

To a solution of 3-cyanoindole (1.0 g, 7.03 mmol) in DMC (10 mL), DABCO(0.079 g, 0.70 mmol) is added and the resulting solution is heated toreflux for 8 h. The reaction is cooled to RT, and diluted with EtOAc (40mL) and H₂O (40 mL). The organic layer is separated and washed insequence with H₂O (50 mL), 10% aqueous citric acid (2×40 mL) and H₂O(4×40 mL). The organic layer is dried over anhydrous Na₂SO₄, filteredand concentrated under vacuum to give 3-cyano-1-methylindole (about 1.08g, 98%) as an oil: ¹H NMR (CDCl₃) δ7.74 (d, 1H), 7.53 (s, 1H), 7.40-7.28(m, 3H), 3.83 (s, 3H); ¹³C NMR (CDCl₃) 136.0, 135.6, 127.8, 123.8,122.1, 119.8, 116.0, 110.4, 85.4, 33.6; MS m/z 156 [M+1]⁺.

EXAMPLE 4

To a solution of indole-2-carboxylic acid (1.0 g, 6.21 mmol) in DMC (10mL), DABCO (0.77 g, 6.83 mmol) is added followed by DMF (4 mL) and theresulting solution is heated to 90-95° C. for 21 h. The reaction iscooled to RT, and diluted with EtOAc (50 mL) and H₂O (40 mL). Theorganic layer is separated and washed in sequence with H₂O (50 mL), 10%aqueous citric acid (2×40 mL), saturated agueous sodium bicarbonate(NaHCO₃, 2×40 mL) and H₂O (2×40 mL). The organic layer is dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum to give1-methylindole-2-carboxylate (about 1.12 g, 95%) as a solid: ¹H NMR(CDCl₃) δ7.68 (d, 1H), 7.37-7.29 (m, 3H), 7.15 (app dt, 1H), 4.07 (s,3H), 3.91 (s, 3H); ¹³C NMR (CDCl₃) δ162.6, 139.6, 127.6, 125.8, 125.0,122.6, 120.5, 110.2, 110.22, 110.18, 51.6, 31.64; MS m/z 189 [M+1]⁺.

EXAMPLE 5

To a solution of carbazole (1.03 g, 6.16 mmol) in DMC (10 mL), DABCO(0.069 g, 0.62 mmol) is added and the resulting solution is heated to90-95° C. for 24 h. The reaction is cooled to RT, and diluted with EtOAc(40 mL) and H₂O (40 mL). The organic layer is separated and washed insequence with H₂O (50 mL), 10% aqueous citric acid (2×40 mL) and H₂O(3×40 mL). The organic layer is dried over anhydrous Na₂SO₄, filteredand concentrated under vacuum to give 9-methylcarbazole (about 1.08 g,97%) as a beige solid: ¹H NMR (CDCl₃) δ8.06 (d, 2H), 7.43 (t, 2H), 7.31(d, 2H), 7.20 (t, 2H), 3.71 (s, 3H); ¹³C NMR (CDCl₃) δ141.0, 125.7,122.8, 120.3, 118.9, 108.5, 29.0; MS m/z 181 [M+1]⁺.

EXAMPLE 6

The title compound is prepared analogously to the previous Examples inabout 97% yield: ¹H NMR (CDCl₃) δ7.62 (d, 1H), 7.32 (d, 1H), 7.22 (t,1H), 7.12 (t, 1H), 7.04 (d, 1H), 6.48 (d, 1H) 3.78 (s, 3H); ¹³C NMR(CDCl₃) δ136.7, 128.8, 128.5, 121.5, 120.9, 119.3, 109.2, 100.9, 32.8;MS m/z 131 [M+1]⁺.

EXAMPLE 7

The title compound is prepared analogously to the previous Examples inabout 95% yield: ¹H NMR (CDCl₃) δ8.57 (d, 1H), 8.11 (dd, 1H), 7.33 (d,1H), 7.21 (d, 1H), 6.67 (d, 1H), 3.86 (s, 3H); ¹³C NMR (CDCl₃) δ141.5,139.4, 132.0, 127.6, 118.2, 117.2, 109.1, 103.8, 33.3; MS m/z 176[M+1]⁺.

EXAMPLE 8

The title compound is prepared analogously to the previous Examples inabout 97% yield: ¹H NMR (CDCl₃) δ7.66 (d, 1H), 7.53-7.35 (m, 6H), 7.25(dd, 1H), 7.14 (t, 1H), 6.57 (s, 1H), 3.75 (s, 3H); ¹³C NMR (CDCl₃)δ141.5, 138.3, 132.8, 129.3, 128.5, 127.9, 127.8, 121.6, 120.5, 119.8,109.6, 101.6, 31.1; MS m/z 208 [M+1]⁺.

EXAMPLE 9

To a mixture of 5-bromoindole (392 mg, 2.0 mmol), DBC (726 mg, 3.0 mmol)and DABCO (22.4 mg, 0.2 mmol) is added DMA (4 mL). The resultingsolution is heated at 135° C. for 24 h. The reaction mixture is cooledto RT and diluted with EtOAc (50 mL) and H₂O (50 mL). The two layers areseparated and the aqueous layer is back extracted with EtOAc (50 mL).The combined organic layers are washed with brine and dried overanhydrous Na₂SO₄. The mixture is filtered and concentrated under vacuum.The crude residue is purified with Biotage Flash Chromatography unit on40 s cartridge eluting with hexane:CH₂Cl₂=19:1 solvent mixture to afford5-bromo-1-benzylindole (about 451.9 mg, 79%) as a white solid: mp 90°C.; ¹H NMR (CDCl₃) δ7.68 (d, 1H), 7.16 (m, 4H), 7.04 (m, 4H), 6.40 (d,1H), 5.20 (s, 2H); ¹³C NMR (CDCl₃) δ137.0, 134.9, 130.4, 129.4, 128.8,127.7, 126.6, 124.5, 123.4, 112.8, 111.1, 101.2, 50.2; MS m/z 285.0150[M+1]⁺.

EXAMPLE 10

The title compound is prepared analogously to example 9 in about 90%yield as a white solid: mp 103° C.; ¹H NMR (CDCl₃) δ8.45 (d, 1H), 7.91(dd, 1H), 7.15 (m, 5H), 6.95 (m, 2H), 6.57 (d, 1H), 5.21 (s, 2H); ¹³CNMR (CDCl₃) δ141.7, 139.0, 136.1, 131.4, 129.0, 128.1, 127.9, 126.7,118.2, 117.4, 109.6, 104.4, 50.6; MS m/z 252.0892 [M+1]⁺.

EXAMPLE 11

To a mixture of indole (234 mg, 2.0 mmol), DBC (726 mg, 3.0 mmol), DABCO(67.2 mg, 0.6 mmol) and TBAC (556 mg, 2.0 mmol) is added DMA (4 mL). Theresulting solution is heated at 135° C. for 2 h. The reaction mixture iscooled to RT and diluted with EtOAc (50 mL) and H₂O (50 mL). The twolayers are separated and the aqueous layer is back extracted with EtOAc(50 mL). The combined organic layers are washed with brine and driedover anhydrous Na₂SO₄. The mixture is filtered and concentrated undervacuum. The crude residue is purified with Biotage Flash Chromatographyunit on 40 s cartridge eluting with hexane:CH₂Cl₂=19:1 solvent mixtureto afford 1-benzylindole (about 331.2 mg, 80%) as a white solid: mp 43°C.; ¹H NMR (CDCl₃) δ7.38 (m, 9H), 6.73 (d, 1H), 5.48 (s, 2H); ¹³C NMR(CDCl₃) δ137.5, 136.3, 128.7, 128.2, 127.6, 126.7, 121.6, 120.9, 119.5,109.7, 101.6, 50.0; MS m/z 207.1043 [M+1]⁺.

EXAMPLE 12

A mixture of carbazole (167 mg, 1.0 mmol), DBC (363 mg, 1.5 mmol), DABCO(33.6 mg, 0.3 mmol) and TBAC (2.0 g) is heated at 135° C. for 1 h. Asmall sample is taken from the melt, cooled down to RT, and added amixture of H₂O (1 mL) and Et₂O (1 mL). The organic layer is separatedand Et₂O is evaporated. The residue is dissolved into a mixture ofH₂O:CH₃CN=1:1 (1 mL) and subjected to a HPLC analysis on Waters 717 HPLCinstrument with Symmetry Shield RP₈ 3.9×150 mm column eluting with50:50H₂O:CH₃CN solvent mixture at 40° C. Chromatogram indicated about91% conversion to the desired product 1-benzylcarbazole.

EXAMPLE 13

A mixture of 5-bromoindole (3.92 g, 20 mmol), DBC (14.52 g, 60 mmol),DABCO (224 mg, 2.0 mmol) and TBAC (5.56 g, 20 mmol) is dissolved inCH₃CN (80 mL). The resulting solution is subjected to microwaveirradiation by passing through (flow rate=20 mL/min) a MilestoneETHOS-CFR continuous-flow reactor, which is preheated at 160° C. under20 bar pressure. After the first pass (6 min) the reaction mixture iscollected and cooled to ambient temperature. The mixture is concentratedunder vacuum. The residue is diluted with EtOAc and H₂O. The two layersare separated and the aqueous layer is back extracted with EtOAc. Thecombined organic layers are washed with brine and dried over anhydrousNa₂SO₄. The mixture is filtered and concentrated under vacuum. The cruderesidue is purified with Biotage Flash Chromatography unit on 40 scartridge eluting with hexane:CH₂Cl₂=19:1 solvent mixture to afford5-bromo-1-benzylindole (about 76% yield) as a white solid: mp 90° C.; ¹HNMR, ¹³C NMR and MS data match the ones reported in Example 9.

EXAMPLE 14

A mixture of carbazole (3.34 g, 20 mmol), DBC (14.52 g, 60 mmol), DABCO(672 mg, 6.0 mmol) and TBAC (5.56 g, 20 mmol) is dissolved in CH₃CN (80mL). The resulting solution is subjected to microwave irradiation bypassing through (flow rate 20 mL/min) a Milestone ETHOS-CFR continuousflow reactor, which is preheated at 160° C. under 20 bar pressure. Afterthe third pass (18 min), the reaction mixture is collected and cooled toRT. The mixture is concentrated under vacuum. The residue is dilutedwith EtOAc and H₂O. The two layers are separated and the aqueous layeris back extracted with EtOAc. The combined organic layers are washedwith brine and dried over anhydrous Na₂SO₄. The mixture is filtered andconcentrated under vacuum. The crude residue is purified with BiotageFlash Chromatography unit on 40 s cartridge eluting withhexane:CH₂Cl₂=19:1 solvent mixture and afforded 1-benzylcarbazole (about76% yield) as a white solid: mp 117° C.; ¹H NMR (CDCl₃) δ8.05 (d, 2H),7.20 (m, 11H), 5.42 (s, 2H); ¹³C NMR (CDCl₃) δ140.6, 137.1, 128.7,127.4, 126.4, 125.8, 123.0, 120.3, 119.1, 46.5; MS m/z 257.1202 [m+1]⁺.

1. A method for the preparation of indole derivatives of the formula

wherein X is methyl; and R₁ and R₂ are independently hydrogen oroptionally substituted alkyl, R₃ is halogen; and R₄ is hydrogen,halogen, cyano, nitro, hydroxyl, optionally substituted alkyl, alkoxy,aralkoxy, carboxy, alkoxycarbonyl, aryl, or heteroaryl; which methodcomprises reacting indoles of the formula

wherein R₁, R₂, R₃ and R₄ have meanings as defined for formula I; withdimethyl carbonate when X is methyl; in the presence of a catalyticamount of 1,4-diazabicyclo[2.2.2]octane at an ambient temperature. 2.The method according to claim 1, wherein the molar ratio of1,4diazabicyclo[2.2.2]octane to the compound of formula II initiallypresent in the reaction mixture ranges from 0.01:1 to 0.5:1.
 3. Themethod according to claim 2, wherein the molar ratio of the base to thecompound of formula II initially present in the reaction mixture rangesfrom 0.05:1 to 0.15:1.
 4. The method according to claim 2, wherein theambient temperature ranges from 80° C. to 100° C.
 5. The methodaccording to claim 2, wherein the reaction is carried out in thepresence of an organic solvent.
 6. The method according to claim 5,wherein the organic solvent is selected from the group consisting oftoluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide andN-methylpyrrolidinone.
 7. The method according to claim 6, wherein theorganic solvent is N,N-dimethyl-formamide.
 8. The method according toclaim 7, wherein the ambient temperature ranges from 90° C. to 95° C. 9.The method according to claim 2, wherein the reaction is carried out inthe presence of an ionic liquid.
 10. The method according to claim 9,wherein the ionic liquid is tetra-n-butylammonium chloride.
 11. Themethod according to claim 2, wherein the reaction is conducted undermicrowave irradiation at a frequency from 300 MHz to 30 GHz, and at atemperature ranging from 80° C. to 300° C. for a period of microwaveirradiation time ranging from 1 second to 300 min.